Our research aims to explore the role and regulation of protein synthesis in normal and diseased states using human and other mammalian cell lines, mouse models, and murine adult stem cell systems. Protein synthesis is a fascinating system that ensures organismal homeostasis by controlling the quantity and quality of the proteome. Regulation of gene expression at the translational level provides a temporal advantage by eliciting rapid fluctuations in protein levels in response to changes in the cellular environment. Protein synthesis is one of the most energy demanding processes in the cell and the high-energy cost of protein production requires the cell to closely monitor and regulate the translational machinery to ensure proper growth and survival under conditions of stress. In response to diverse physiological and pathological states, several signaling pathways are activated that converge on the translational machinery to alter the rates and types of protein being synthesized. The pervasiveness of translational control is evident in the genesis and progression of diseases such as cancer that are often a consequence of deregulated protein synthesis. Such deregulation presents an excellent opportunity to selectively target the translational machinery for therapeutic advancement.

Our research work is currently focused on the following three main areas of research:

Regulation of eukaryotic initiation factors (eIFs):

Eukaryotic protein synthesis is predominantly regulated at the initiation stage. Translation is initiated by the recognition of the 5' cap (or IRES) of mRNA followed by the recruitment of the 40S ribosomal subunit onto mRNA and start codon recognition. These key steps in initiation are tightly controlled by the eIFs and are also influenced by elements in the 5'UTR, ORF and 3'UTR of individual mRNAs. Based on the cellular context, upstream signaling pathways regulate eIFs by altering their levels, or their activities via post-translational modifications such as methylation, phosphorylation, acetylation or by reorganizing their spatial distribution. Our recent work has identified novel post-translational modifications of eIFs that is dependent on the state of growth or stress. We are currently exploring the role of these post-translational modifications in altering eIFs function in initiating global translation or translation of selective mRNAs, and their influence on cellular growth and survival.

Translational Control of Cancer: The uncontrolled growth and proliferation of cancer cells are sustained by a reciprocal increase in ribosome biogenesis and protein synthesis rates. We are interested in understanding the contributions of translational control towards tumor initiation and progression towards malignancy. We are currently investigating the signaling program mediated by the Ras oncogene and its influence on eIFs and other translational factors. These efforts will help to identify novel targets that will eventually provide a parallel or alternate means for cancer therapeutics.

Protein synthesis in adult stem cells: Adult stem cells are essential for maintaining tissue integrity by serving as a renewed source of cells. Interestingly, most adult stem cells exhibit lower rates of protein synthesis compared to their progenitor cells. It is unclear as to how such low rates of protein synthesis are maintained in stem cells and how they influence the stem cell response to stress. Protein synthesis regulation in adult stem cells is vastly under explored. We are interested in understanding the mechanisms that regulate the translation initiation machinery and its influence on the protein synthesis rates in murine adult stem cells. These efforts will help us to gain a better understanding of the basic biology of adult stem cells.